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Reducing the Levels of Akt Activation by PDK1 Knock-in Mutation Protects Neuronal Cultures against Synthetic Amyloid-Beta Peptides
Yang, Shaobin (Universitat Autònoma de Barcelona. Institut de Neurociències)
Pascual-Guiral, Sònia (Universitat Autònoma de Barcelona. Institut de Neurociències)
Ponce, Rebeca (Universitat Autònoma de Barcelona. Institut de Neurociències)
Giménez Llort, Lydia (Universitat Autònoma de Barcelona. Institut de Neurociències)
Baltrons Soler, Ma. Antonia (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Arancio, Ottavio (Columbia University)
Palacio Cornide, José Ramón (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Clos, Victòria (Universitat Autònoma de Barcelona. Institut de Neurociències)
Yuste Mateos, Víctor J. (Víctor José) (Universitat Autònoma de Barcelona. Institut de Neurociències)
Bayascas Ramírez, José Ramón (Universitat Autònoma de Barcelona. Institut de Neurociències)

Date: 2018
Abstract: The Akt kinase has been widely assumed for years as a key downstream effector of the PI3K signaling pathway in promoting neuronal survival. This notion was however challenged by the finding that neuronal survival responses were still preserved in mice with reduced Akt activity. Moreover, here we show that the Akt signaling is elevated in the aged brain of two different mice models of Alzheimer Disease. We manipulate the rate of Akt stimulation by employing knock-in mice expressing a mutant form of PDK1 (phosphoinositide-dependent protein kinase 1) with reduced, but not abolished, ability to activate Akt. We found increased membrane localization and activity of the TACE/ADAM17 α-secretase in the brain of the PDK1 mutant mice with concomitant TNFR1 processing, which provided neurons with resistance against TNFα-induced neurotoxicity. Opposite to the Alzheimer Disease transgenic mice, the PDK1 knock-in mice exhibited an age-dependent attenuation of the unfolding protein response, which protected the mutant neurons against endoplasmic reticulum stressors. Moreover, these two mechanisms cooperatively provide the mutant neurons with resistance against amyloid-beta oligomers, and might singularly also contribute to protect these mice against amyloid-beta pathology.
Note: Número d'acord de subvenció MINECO/SAF2014-52813-R
Rights: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Language: Anglès
Document: article ; recerca ; publishedVersion
Subject: PDK1/Akt ; Knock-in mouse ; Alzheimer disease ; TACE a-secretase ; Unfolding protein response
Published in: Frontiers in aging neuroscience, Vol. 9 (January 2018) , art. 435, ISSN 1663-4365

DOI: 10.3389/fnagi.2017.00435
PMID: 29358916

19 p, 7.5 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (scientific output) > Health sciences and biosciences > Institut de Neurociències (INc)
Articles > Research articles
Articles > Published articles

 Record created 2018-01-23, last modified 2020-08-09

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